The human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, particularly of the CD4+ T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDs-related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. Two genetically distinct types of HIV have been identified, HIV-1 and HIV-2 (P. Lemey et al., Proc. Nat. Acad. Sci. USA 2003 100(11):6588-692). Reference to HIV and/or HIV reverse transcriptase herein should be understood to refer to HIV-1 and a reverse transcriptase expressed by the HIV-1 subtype.
In common with other retroviruses, the HIV genome encodes protein precursors known as gag and gag-pol which are processed by a viral protease to afford the protease, reverse transcriptase (RT), endonuclease/integrase and mature structural proteins of the virus core. Interruption of this processing prevents the production of normally infectious virus. Considerable efforts have been directed towards the control of HIV by inhibition of virally encoded enzymes.
Currently available chemotherapy targets two viral enzymes crucial for the production of viral proteins: HIV protease and HIV reverse transcriptase. (J. S. G. Montaner et al. “Antiretroviral therapy: ‘the state of the art”, Biomed. & Pharmacother. 1999 53:63-72; R. W. Shafer and D. A. Vuitton, “Highly active retroviral therapy (HAART) for the treatment of infection with human immunodeficiency virus type”, Biomed. & Pharmacother. 1999 53 :73-86; E. De Clercq, “New Developments in Anti-HIV” Chemotherap. Curr. Med. Chem. 2001 8:1543-1572). Two general classes of RTI inhibitors have been identified: nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors.
NRTIs typically are 2′,3′-dideoxynucleoside (ddN) analogs which must be phosphorylated prior to interacting with viral RT. The corresponding triphosphates function as competitive inhibitors or alternative substrates for viral RT. After incorporation into nucleic acids the nucleoside analogs terminate the chain elongation process. HIV reverse transcriptase has DNA editing capabilities which enable resistant strains to overcome the blockade by cleaving the nucleoside analog and continuing the elongation.
NNRTIs were first discovered in 1989. NNRTIs are allosteric inhibitors which bind reversibly at a non-substrate-binding site on the HIV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity (R. W. Buckheit, Jr., “Non-nucleoside reverse transcriptase inhibitors: perspectives for novel therapeutic compounds and strategies for treatment of HIV infection”, Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Clercq, “The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV infection”, Antiviral Res. 1998 38:153-179; E. De Clercq, “New Developments in Anti-HIV Chemotherapy”, Current Medicinal Chem. 2001 8(13):1543-1572; G. Moyle, “The Emerging Roles of Non-Nucleoside Reverse Transcriptase Inhibitors in Antiviral Therapy”, Drugs 2001 61(1): 19-26). Although over thirty structural classes of NNRTIs have been identified in the laboratory, only three compounds have been approved for HIV therapy: efavirenz, nevirapine and delavirdine.

2-Benzoyl phenyl-N-[phenyl]-acetamide compounds 1a and 1b have been shown to inhibit HIV-1 reverse transcriptase (P. G. Wyatt et al., J. Med. Chem. 1995 38(10):1657-1665). Further screening identified related compounds, e.g. 2-benzoyl phenyloxy-N-[phenyl]-acetamide, 2a, and a sulfonamide derivative 2b which also inhibited reverse transcriptase (J. H. Chan et al., J. Med Chem. 2004 47(5):1175-1182; C. L. Webster et al., WO01/17982). P. Bonneau et al. in US 20060069261 published Mar. 30, 2006 disclose 4-{4-[2-(2-benzoyl-phenoxy)-acetylamino]-phenyl}-2,2-dimethyl-but-3-ynoic acid compounds 3 which are inhibitors of HIV reverse transcriptase.

Pyridazinone non-nucleoside reverse transcriptase inhibitors 4 have been described by J. P. Dunn et al. in U.S. Publication filed Mar. 23, 2004 and by J. P. Dunn et al. in U.S. Publication No. 2005021554 filed Mar. 22, 2005. 5-Aralkyl-2,4-dihydro-[1,2,4]triazol-3-one, 5-aralkyl-3H-[1,3,4]oxadiazol-2-one and 5-aralkyl-3H-[1,3,4]thiadiazol-2-one non-nucleoside reverse transcriptase inhibitors 5 have been disclosed by J. P. Dunn et al. in U.S. Publication No. 20040192704 filed Mar. 23, 2004 and by J. P. Dunn et al. in U.S. Publication No. 20060025462 filed Jun. 27, 2005. Phenylacetamide non-nucleoside reverse transcriptase inhibitors 6 have been disclosed by J. P. Dunn et aL in U.S. Pub. No. 20050239881 published Oct. 27, 2005 and methods for treating retroviral infection with phenylacetamide compounds have been disclosed by J. P. Dunn et al. in U.S. Publication No. 20050239880 published Oct. 27, 2005; T. Mirzadegan and T. Silva in U.S. Ser. No. 60/728,443 filed Oct. 19, 2005; and Z. K. Sweeney and T. Silva in U.S. Ser. No 60/728,609 Oct. 19, 2005. These applications are hereby incorporated by reference in their entirety.

In WO2006/067587 published Jun. 26, 2006, L. H. Jones et al. disclose biaryl ether derivatives and compositions containing them which bind to the enzyme reverse transcriptase and are modulators, especially inhibitors, thereof.